The present invention relates generally to shipping and/or storage of thermally sensitive materials and more particularly to freeze protective units suitable for use in the transport and storage of products such as those biologically active proteins which may be susceptible to irreversible physicochemical alteration upon freezing.
The art is rich in proposal for the development of insulated storage and transport containers adapted to protect various thermosensitive products such as foodstuffs, medicaments, acrylic paints and the like from damage. While a major focus of such developments has been the protection of thermosensitive products from the adverse effects of elevated temperatures (see, e.g., U.S. Pat. No. 4,903,493), devices have also been developed which function to inhibit product freezing and still other shipping and storage units have been devised for the purpose of insulating products from exposure to both high and low temperature extremes. U.S. Pat. No. 4,738,364, for example, proposes to address the problems associated with safeguarding medicines from reaching either high or low temperature thresholds. Despite the continuous development of increasingly efficient insulating containers for shipment of thermosensitive products, the costs of highly efficient thermal protection are most often balanced against the statistical likelihood of exposure to temperature extremes. The result is that such products are transported and stored in a manner providing protection for most, but certainly not all product shipments. Where the adverse effects of product exposure to temperature extremes are manifest, this presents little risk to the ultimate consumer. Where such effects cannot be readily ascertained, as is frequently the case with medicaments, the risks associated with consumer use of thermally damaged products are significantly increased.
With the recent development of recombinant DNA technologies, increasing numbers of biologically active materials such as peptides, proteins and glycoproteins have become available for research and therapeutic use. Because these products have a significant potency even when administered in minute quantities, they are frequently supplied as dilute aqueous solutions of the active ingredient combined with small quantities of pharmaceutically acceptable adjuvant and carrier substances such as serum albumin. Studies of the effects of temperature extremes on these compositions have surprisingly revealed that freezing can generate physicochemical alterations which are not spontaneously reversible upon thawing. More specifically, the freezing of dilute solutions of biologically active human proteins has been seen to give rise to the formation of both lower and higher molecular weight species of the proteins. These observations have expectedly prompted concern regarding the maintenance of biological potency of the products which have been subjected to freezing. They have also generated significant concerns in an immunological context. To the extent that the observed formation of higher molecular weight species of proteins is reflective of the formation of aggregates of either the projected therapeutic protein with other protein molecules or with non-protein components of the formulation, there is a potential risk that the recipient may develop adverse immunological responses. Such potential risks are, of course, exacerbated by the fact that visual inspection of, e.g., a unit dosage vial containing a solution of a therapeutic protein is insufficient to reveal that the product has undergone freezing at some time during its transport or storage and may therefore contain undesired protein fragments or aggregates.
Consistent with the above, there can be seen to exist a need in the art for new freeze protective packaging units useful in the transport and storage of biologically active products such as those protein solutions which can be susceptible to visually occult physicochemical alteration upon freezing. Ideally, such packaging would allow for the protected transport of therapeutic proteins in the unit dosage glass vials ordinarily employed as containers for therapeutic agents. Desirably, such packaging would facilitate transport in a refrigerated, but not frozen, state and would insulate the contents of the vials against freezing when exposed to extreme cold temperatures such as might occasionally be encountered in the projected distribution environment. The packaging should be cost effective to the extent that it would allow freeze protection in most ordinary transport and storage circumstances. When extraordinarily cold temperatures are nonetheless encountered, the freeze protective packaging would ideally provide means for an after-the-fact determination that the containers have been exposed to the extreme conditions which might cause irreversible physicochemical alteration.